ABSTRACT
Objective To explore the therapeutic effects of sirolimus on nephritic mice with chronic rejection, and the possible mechanisms. Methods B6D2F1 mice transplanted with cell mixture of spleen, thymus, and lymph nodes from DBA/2 spleen, thymus, and lymph nodes cell mixture were used to construct murine model with chronic rejection, and the transplanted mice were randomly divided into two groups. Mice in the sirolimus-treated group were given sirolimus orally in a dose of 1 mg(kg*d) for 12 consecutive weeks, while mice in the control group were administered with equal amounts of olive oil. Nephritis in mice was confirmed by urine protein determination and histopathological analysis. Enzyme immunoassay was used to detect the serum levels of anti-DNA antibodies including anti-ds DNA IgG, anti-ds DNA IgG1, anti-ds DNA IgG2a, anti-ss DNA IgG, anti-ss DNA IgG1, and anti-ss DNA IgG 2a. Real-time PCR analysis was conducted to evaluate the gene expression of interleukin-6 (IL-6), tumor necrosis factor-α (α), interferon-γ (IFN-γ), interleukin-1 β (IL-lβ), monocyte chemoattractant protein 1 (MCP-1), regulated upon activation n T cell expressed and secreted (RANTES), B lymphocyte chemoattractant (BLC), transforming growth factor βi (TGF-βi), and gen I. The proportion and activation of T and B lymphocytes in peripheral blood or spleen were determined by flow cytometric ana Results At the end of observation period, the incidence of nephritis in mice treated with sirolimus was significantly lower than t mice treated with olive oil (P < 0. 05). Histopathological evaluation of kidney specimen showed evident vascular intimal hyper and mononuclear cell infiltration in control group. In contrast, no obvious kidney lesions was observed in sirolimus-treated mice. thermore, the levels of anti-DNA antibodies and the transcriptional expression of lupus IL-6, TNF-α, IFN-γ, IL-lβ, MCP-1, ] TES, BLC, TGF-βi, and collgen I were significantly down-regulated in sirolimus-treated group as compared with control group. cytometric analysis indicated that both of the proportion of activated/memory T cells in peripheral blood and the expression level o face activation markers on T and B lymphocytes in spleen were significantly decreased in mice exposed to sirolimus as comparec those exposed to olive oil (P <0. 05). On the other hand, the proportion of CD4 + FOXP3 + regulatory T cells in spleen was si cantly upregulated in sirolimus-treated group as compared with control group. Conclusion Sirolimus may inhibit the proliferatio activation of effector cells and downregulate the expression of chemokines and inflammatory factors through up-regulation of (FOXP3 3T cells, thus effectively ameliorating the progression of nephritis in mice.
ABSTRACT
Fingolimod (FTY720), a novel immunosuppressive agent, is synthesized by modification of myriocin (ISP-1) from a raditional Chinese herbal medicine Isaclaria sinclrii. Unlike he traditional immunosuppressive agents, fingolimod exerts immunosuppressive and mmunoregulatory functions mainly hrough nteraction with shhingosine-1-phosphate receptors (SIPR) on he cell surface without affecting activation and proliferation of lymphocytes. This article briefly reviews the effects of fingolimod on he distribution and cytokine production of lymphocytes as well as natural immune cells (dendritic cell, macrophage, natural killer cell and natural killer T cell), suggesting he mmunosuppression and mmune regulation functions of fingolimod n nflammation. Then he atest research progress about the herapeutic application of fingolimod n autoimmune diseases, graft-versus-host diseases and umors, the adverse effects of fingolimod and possible solutions are summarized.